US11744879B2 - Recombinant FSH composition for controlled ovarian stimulation - Google Patents

Recombinant FSH composition for controlled ovarian stimulation Download PDF

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US11744879B2
US11744879B2 US16/642,777 US201816642777A US11744879B2 US 11744879 B2 US11744879 B2 US 11744879B2 US 201816642777 A US201816642777 A US 201816642777A US 11744879 B2 US11744879 B2 US 11744879B2
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amh
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treatment
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Joan-Carles ARCE SAEZ
Lisbeth HELMGAARD
Bjarke Mirner Klein
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Ferring BV
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/24—Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g. HCG; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/26—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against hormones ; against hormone releasing or inhibiting factors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere

Definitions

  • the present invention relates to compositions and pharmaceutical products for the treatment of infertility.
  • ART Assisted reproductive technology
  • IVF in vitro fertilisation
  • COS controlled ovarian stimulation
  • FSH gonadotrophins
  • LH luteinising hormone
  • compositions generally used for COS include recombinant follicle stimulating hormone (rFSH) including Rekovelle® and Gonal F, urinary derived FSH, recombinant FSH+LH preparations, urinary derived menotrophin [human menopausal gonadotrophin (hMG)] and highly purified human menopausal gonadotrophin (HP-hMG).
  • IVF can be associated with a risk of ovarian hyperstimulation syndrome (OHSS), which can be life threatening in severe cases.
  • the ability to predict the response potential of women to controlled ovarian stimulation may allow the development of individualised COS protocols. Such individualised protocols could, for example, reduce the risk of OHSS in women predicted to have an excessive response to stimulation, and/or improve pregnancy outcomes in women classed as poor responders.
  • the serum concentration of anti-Müllerian hormone (AMH) is now established as a reliable marker of ovarian reserve. Decreasing levels of AMH are correlated with reduced ovarian response to gonadotrophins during COS. Further, high levels of AMH are a good predictor of excessive ovarian response, and an indicator of risk of OHSS.
  • FSH is naturally secreted by the anterior pituitary gland and functions to support follicular development and ovulation.
  • FSH comprises a 92 amino acid alpha sub-unit, also common to the other glycoprotein hormones LH and CG, and a 111 amino acid beta sub-unit unique to FSH that confers the biological specificity of the hormone (Pierce and Parsons, 1981).
  • Each sub-unit is post translationally modified by the addition of complex carbohydrate residues.
  • Both subunits carry 2 sites for N-linked glycan attachment, the alpha sub-unit at amino acids 52 and 78 and the beta sub-unit at amino acid residues 7 and 24 (Rathnam and Saxena, 1975, Saxena and Rathnam, 1976).
  • FSH is thus glycosylated to about 30% by mass (Dias and Van Roey. 2001. Fox et al. 2001).
  • FSH purified from post-menopausal human urine has been used for many years in infertility treatment; both to promote ovulation in natural reproduction and to provide oocytes for assisted reproduction technologies.
  • FSH recombinant FSH
  • follitropin alfa GONAL-F, Merck Serono/EMD Serono
  • follitropin beta PUREGON/FOLLISTIM, MSD/Schering-Plough
  • FSH FSH
  • isoforms exhibit identical amino acid sequences but differ in the extent to which they are post-translationally modified; particular isoforms are characterised by heterogeneity of the carbohydrate branch structures and differing amounts of sialic acid (a terminal sugar) incorporation, both of which appear to influence the specific isoform bioactivity.
  • Glycosylation of natural FSH is highly complex.
  • the glycans in naturally derived pituitary FSH can contain a wide range of structures that can include combinations of mono-, bi-, tri- and tetra-antennary glycans (Pierce and Parsons, 1981. Ryan et al., 1987. Baenziger and Green, 1988).
  • the glycans can carry further modifications: core fucosylation, bisecting glucosamine, chains extended with acetyl lactosamine, partial or complete sialylation, sialylation with ⁇ 2,3 and ⁇ 2,6 linkages, and sulphated galactosamine substituted for galactose (Dalpathado et al., 2006).
  • the glycosylation of recombinant FSH products reflects the range of glycosyl-transferases present in the host cell line.
  • Commercially available rFSH products derived from engineered Chinese hamster ovary cells (CHO cells) have a more limited range of glycan modifications than those found on the natural products.
  • Examples of the reduced glycan heterogeneity found in CHO cell derived rFSH include a lack of bisecting glucosamine and a reduced content of core fucosylation and acetyl lactosamine extensions (Hard et al., 1990).
  • CHO cells are only able to add sialic acid using the ⁇ 2,3 linkage (Kagawa et al, 1988, Takeuchi et al, 1988, Svensson et al., 1990); CHO cell derived rFSH only includes ⁇ 2,3-linked sialic acid and does not include ⁇ 2,6-linked sialic acid.
  • CHO cell derived FSH is different from naturally produced FSH (e.g. human pituitary/serum/urinary FSH) which contains glycans with a mixture of ⁇ 2,3 and ⁇ 2,6-linked sialic acid, with a predominance of the former.
  • FSH e.g. human pituitary/serum/urinary FSH
  • the amino acid sequence of the human cell line derived recombinant FSH which is the subject of International Patent Application No. PCT/GB2009/000978, published as WO2009/127826A, is the native sequence and is identical to natural human FSH and existing CHO-derived rFSH products.
  • human derived recombinant FSH products i.e. recombinant FSH produced or expressed in a human cell line e.g. made by engineering a human cell line
  • a mixture of both ⁇ 2,3 and ⁇ 2,6-linked sialic acid may be particularly effective when utilised in (e.g. individualised) COS protocols.
  • REKOVELLE® follitropin delta, also known as FE999049
  • human rFSH a human cell line derived recombinant follicle stimulating hormone
  • ART assisted reproductive technologies
  • IVF in vitro fertilisation
  • ICSI intracytoplasmic sperm injection
  • REKOVELLE® is the first rFSH to be derived from a human cell line.
  • the REKOVELLE® (follitropin delta) product is produced by the methods disclosed in International Patent Application No. PCT/GB2009/000978.
  • AMH multi-centre phase 2 anti-Müllerian hormone
  • FE 999049 In the European dose-response phase 2 trial, five doses of FE 999049 ranging from 5.2 ⁇ g/day to 12.1 ⁇ g/day were investigated and a reference group of an approved rFSH product (GONAL-F, 150 IU/day) was also included. In the Japanese dose-response phase 2 trial, three doses of FE 999049 (6 ⁇ g/day, 9 ⁇ g/day and 12 ⁇ g/day) were investigated and a standard therapy of the approved rFSH product (FOLLISTIM, 150 IU/day) was also included. At present, follitropin beta (FOLLISTIM) is the only medicinal product approved in Japan for controlled ovarian stimulation in IVF/ICSI cycles.
  • FOLLISTIM follitropin beta
  • REKOVELLE is individualised for each patient and aims to obtain an ovarian response which is associated with a favourable safety/efficacy profile, i.e. aims to achieve an adequate number of oocytes retrieved and reduce the interventions to prevent ovarian hyperstimulation syndrome (OHSS).
  • REKOVELLE is dosed in micrograms.
  • the individual daily dose will be determined on the basis of the woman's serum anti-Müllerian hormone (AMH) concentration and her body weight.
  • the dose should be based on a recent determination of AMH (i.e. within the last 12 months) measured by the following diagnostic test from Roche: ELECSYS AMH Plus immunoassay.
  • the individual daily dose is to be maintained throughout the stimulation period.
  • the dose is to be rounded off to the nearest 0.33 micrograms to match the dosing scale on the injection pen.
  • the maximum daily dose for the first treatment cycle is 12 micrograms.
  • the body weight is to be measured without shoes and overcoat just prior to start of stimulation.
  • Treatment with REKOVELLE should be initiated day 2 or 3 after start of menstrual bleeding, and continue until adequate follicular development ( ⁇ 3 follicles ⁇ 17 mm) has been achieved, which on average is by the ninth day of treatment (range 5 to 20 days).
  • a single injection of 250 micrograms recombinant human chorionic gonadotropin (hCG) or 5,000 IU hCG is administered to induce final follicular maturation.
  • hCG human chorionic gonadotropin
  • treatment with REKOVELLE should be stopped and triggering of final follicular maturation with hCG should not be performed.
  • the daily dose of REKOVELLE should be maintained or modified according to the patient's ovarian response in the previous cycle. If the patient had adequate ovarian response in the previous cycle without developing OHSS, the same daily dose should be used. In case of ovarian hypo-response in the previous cycle, the daily dose in the subsequent cycle should be increased by 25% or 50%, according to the extent of response observed. In case of ovarian hyperresponse in the previous cycle, the daily dose in the subsequent cycle should be decreased by 20% or 33%, according to the extent of response observed. In patients who developed OHSS or were at risk of OHSS in a previous cycle, the daily dose for the subsequent cycle is 33% lower than the dose the cycle where OHSS or risk of OHSS occurred. The maximum daily dose is 24 micrograms.
  • ESTHER-1 trial was conducted in 1,326 IVF/ICSI patients who were randomised 1:1 to controlled ovarian stimulation with one of the following treatments: 1) FE 999049 in its individualised dosing regimen with the daily dose fixed throughout simulation, or 2) an approved CHO-derived rFSH product (follitropin alfa, GONAL-F) at a standard starting dose of 150 IU/day followed by dose adjustments based on the subject's follicular response during stimulation.
  • FE 999049 in its individualised dosing regimen was demonstrated to be non-inferior to follitropin alfa with respect to ongoing pregnancy rate (30.7% versus 31.6%) and ongoing implantation rate (35.2% versus 35.8%).
  • OHSS ovarian hyperstimulation syndrome
  • the individualised dosing regimen of FE 999049 was associated with a statistically significant reduction in the proportion of subjects with early OHSS and/or preventive interventions for early OHSS in comparison to the standard regimen of CHO-derived rFSH product, with an incidence of 4.7% in the FE 999049 group and 6.2% in the follitropin alfa group.
  • the dose protocol set out in Table A goes some way to mitigating this risk because patients are dosed by bodyweight.
  • very low doses of gonadotropins are potentially associated with inadequate follicular recruitment and poor ovarian response.
  • dosing according to the Table A protocol might lead to very light patients with high AMH receiving a dose of FSH which may be sub-optimal from an efficacy perspective.
  • the present applicants identified patients in the Japanese phase 2 trial mentioned above (see also Example 2 below) who (based on AMH and body weight) would have received ⁇ 6 ⁇ g FE 999049 according to the individualised FE 999049 dosing regimen set out in Table A, but actually received either 6 ⁇ g FE 999049 or 150 IU FOLLISTIM as per randomisation. This was only a very limited number of patients (5 patients in the 6 ⁇ g FE 999049 group, and 3 patients in the 150 IU FOLLISTIM group). Surprisingly, ovarian response of 15 oocytes or more was not observed in any of the 5 patients in the 6 ⁇ g FE 999049 group but in 2 of 3 patients (66.7%) in the 150 IU FOLLISTIM group.
  • a composition for use in the treatment of infertility in a patient (e.g. a female patient) having AMH ⁇ 15 pmol/L (for example AMH ⁇ 16 pmol/L, for example AMH ⁇ 19 pmol/L, for example AMH ⁇ 26 pmol/L, for example AMH ⁇ 28 pmol/L, for example AMH ⁇ 40 pmol/L) and bodyweight ⁇ 60 kg, the composition comprising a daily dose of, or a daily dose equivalent to, 6 to 8 ⁇ g recombinant FSH.
  • the composition comprises a daily dose of 6 to 8 ⁇ g recombinant FSH. More preferably, the composition comprises a daily dose of 6 ⁇ g recombinant FSH.
  • the treatment of infertility may include a step (or steps) of determining the serum AMH level and bodyweight of the patient.
  • the treatment of infertility may include a step of administering the dose to the patient having the defined serum AMH level and bodyweight.
  • the treatment of infertility may include a step (or steps) of determining the serum AMH level and bodyweight of the patient, and a step of administering the dose to the patient having AMH 15 pmol/L (for example AMH ⁇ 16 pmol/L, for example AMH ⁇ 19 pmol/L, for example AMH ⁇ 26 pmol/L, for example AMH ⁇ 28 pmol/L, for example AMH ⁇ 40 pmol/L) and bodyweight ⁇ 60 kg [e.g. bodyweight ⁇ 55 kg, for example ⁇ 52 kg, for example ⁇ 50 kg, for example ⁇ 45 kg].
  • the step of determining the serum AMH level of the patient may take place up to twelve months before the dose is first administered to the patient.
  • the serum AMH level of the patient is determined (measured) by the ELECSYS AMH Plus immunoassay (available from Roche, of Switzerland, see www.roche.com).
  • the step of determining the bodyweight of the patient may take place just before (e.g. 0 to 2 days before) the dose is first administered to the patient.
  • the step of determining the bodyweight of the patient may use weighing scales, as are well known.
  • the composition may be for use for treatment of infertility in a patient having bodyweight ⁇ 59 kg, for example ⁇ 56 kg, for example ⁇ 55 kg, for example ⁇ 52 kg, for example ⁇ 50 kg, for example ⁇ 45 kg, for example ⁇ 42 kg, for example ⁇ 31.5 kg.
  • the composition may be for use for treatment of infertility in a patient having bodyweight from 40 to 59.9 kg, for example for treatment of infertility in a patient having bodyweight from 45 to 55 kg.
  • the composition may be for use for treatment of infertility in a patient having AMH ⁇ 16 pmol/L, for example AMH ⁇ 19 pmol/L, for example AMH ⁇ 26 pmol/L, for example AMH ⁇ 28 pmol/L, for example AMH ⁇ 30 pmol/L, for example AMH ⁇ 40 pmol/L.
  • the composition (e.g. pharmaceutical composition) is for use for treatment of infertility in a patient having bodyweight ⁇ 52 kg (for example 50 kg, for example ⁇ 45 kg) and having AMH ⁇ 26 pmol/L (for example AMH ⁇ 28 pmol/L, for example AMH ⁇ 30 pmol/L, for example AMH ⁇ 40 pmol/L).
  • the treatment of infertility may include a step of determining the serum AMH level and bodyweight of the patient, and a step of administering the dose to a patient having AMH ⁇ 26 pmol/L and bodyweight ⁇ 52 kg.
  • a composition for use in the treatment of infertility in a patient (e.g. a female patient) identified (prior to treatment) as having AMH ⁇ 15 pmol/L (for example AMH ⁇ 16 pmol/L, for example AMH ⁇ 19 pmol/L, for example AMH ⁇ 26 pmol/L, for example AMH ⁇ 28 pmol/L, for example AMH ⁇ 40 pmol/L) and identified (prior to treatment) as having bodyweight ⁇ 60 kg, the composition comprising a daily dose of, or a daily dose equivalent to, 6 to 8 ⁇ g recombinant FSH.
  • the composition comprises a daily dose of 6 to 8 ⁇ g recombinant FSH. More preferably, the composition comprises a daily dose of 6 ⁇ g recombinant FSH.
  • the treatment of infertility may include a step of identifying the patient (prior to treatment) based on the serum AMH level and bodyweight of the patient.
  • the treatment of infertility may include a step of administering the dose to the patient identified as having the defined serum AMH level and bodyweight.
  • the treatment of infertility may include a step of identifying the patient (prior to treatment) based on the serum AMH level and bodyweight of the patient, and a step of administering the dose to the patient identified (prior to treatment) as having AMH ⁇ 15 pmol/L (for example AMH ⁇ 16 pmol/L, for example AMH ⁇ 19 pmol/L, for example AMH ⁇ 26 pmol/L, for example AMH ⁇ 28 pmol/L, for example AMH ⁇ 40 pmol/L) and identified (prior to treatment) as having bodyweight ⁇ 60 kg [e.g. bodyweight ⁇ 55 kg, for example ⁇ 52 kg, for example ⁇ 50 kg, for example ⁇ 45 kg].
  • AMH ⁇ 15 pmol/L for example AMH ⁇ 16 pmol/L, for example AMH ⁇ 19 pmol/L, for example AMH ⁇ 26 pmol/L, for example AMH ⁇ 28 pmol/L, for example AMH ⁇ 40 pmol/L
  • bodyweight ⁇ 60 kg e.g
  • the step of identifying the patient (prior to treatment) based on the serum AMH level and bodyweight of the patient may take place just before (e.g. 0 to 2 days before) the dose is first administered to the patient.
  • the step of identifying the patient may be based on a serum AMH level determined previously (e.g. a serum AMH level determined up to twelve months before the dose is first administered to the patient).
  • the serum AMH level of the patient is determined (measured) by the ELECSYS AMH Plus immunoassay (available from Roche, of Switzerland, see www.roche.com).
  • the step of identifying the patient may be based on a bodyweight of the patient determined just before (e.g. 0 to 2 days before) the dose is first administered to the patient.
  • the step of determining the bodyweight of the patient may use weighing scales, as are well known.
  • the composition may be for use for treatment of infertility in a patient identified (prior to treatment) as having bodyweight ⁇ 59 kg, for example ⁇ 56 kg, for example ⁇ 55 kg, for example ⁇ 52 kg, for example ⁇ 50 kg, for example ⁇ 45 kg, for example ⁇ 42 kg, for example ⁇ 31.5 kg.
  • the composition may be for use for treatment of infertility in a patient identified (prior to treatment) as having bodyweight from 40 to 59.9 kg, for example for treatment of infertility in a patient having bodyweight from 45 to 55 kg.
  • the composition may be for use for treatment of infertility in a patient identified (prior to treatment) as having AMH ⁇ 16 pmol/L, for example AMH ⁇ 19 pmol/L, for example AMH ⁇ 26 pmol/L, for example AMH ⁇ 28 pmol/L, for example AMH ⁇ 30 pmol/L, for example AMH ⁇ 40 pmol/L.
  • the composition (e.g. pharmaceutical composition) is for use for treatment of infertility in a patient identified (prior to treatment) as having bodyweight ⁇ 52 kg (for example ⁇ 50 kg, for example ⁇ 45 kg) and identified (prior to treatment) as having AMH ⁇ 26 pmol/L (for example AMH ⁇ 28 pmol/L, for example AMH ⁇ 30 pmol/L, for example AMH ⁇ 40 pmol/L).
  • bodyweight ⁇ 52 kg for example ⁇ 50 kg, for example ⁇ 45 kg
  • AMH ⁇ 26 pmol/L for example AMH ⁇ 28 pmol/L, for example AMH ⁇ 30 pmol/L, for example AMH ⁇ 40 pmol/L.
  • the treatment of infertility may include a step of identifying the patient (prior to treatment) based on the serum AMH level and bodyweight of the patient, and a step of administering the dose to the patient identified (prior to treatment) as having AMH ⁇ 26 pmol/L, and identified (prior to treatment) as having bodyweight ⁇ 52 kg.
  • the FSH is a recombinant FSH (rFSH).
  • the rFSH e.g. human cell line derived recombinant FSH
  • the FSH (rFSH) for use according to the invention may have 1% to 99% of the total sialylation being ⁇ 2,3-sialylation.
  • the FSH (rFSH) according to the invention may have 1% to 99% of the total sialylation being ⁇ 2,6-sialylation.
  • 80 to 95%, for example 80 to 90%, for example 82 to 89%, for example 85 to 89% of the total sialylation is ⁇ 2,3-sialylation.
  • sialylation it is meant the amount of sialic residues present on the FSH carbohydrate structures.
  • ⁇ 2,3-sialylation means sialylation at the 2,3 position (as is well known in the art) and ⁇ 2,6 sialylation at the 2,6 position (also well known in the art).
  • % of the total sialylation may be ⁇ 2,3 sialylation” refers to the % of the total number of sialic acid residues present in the FSH which are sialylated in the 2,3 position.
  • % of the total sialylation being ⁇ 2,6-sialylation refers to the % of the total number of sialic acid residues present in the FSH which are sialylated in the 2,6 position.
  • the rFSH may be present as a single isoform or as a mixture of isoforms.
  • the composition may be for use for treatment of infertility in an Asian patient (e.g. Japanese, Chinese, Korean, Indian patient, for example a patient of Han, Yamato or Korean ethnicity).
  • Asian patient e.g. Japanese, Chinese, Korean, Indian patient, for example a patient of Han, Yamato or Korean ethnicity.
  • a medicament for treatment of infertility in an Asian e.g. Japanese, Chinese, Korean, Indian
  • an Asian e.g. Japanese, Chinese, Korean, Indian
  • FSH follicle stimulating hormone
  • the medicament is administered to an Asian (e.g.
  • the daily dose is 6 to 8 ⁇ g recombinant FSH. More preferably, the daily dose is 6 ⁇ g recombinant FSH.
  • the treatment of infertility may include a step of identifying the patient (prior to treatment) based on the serum AMH level and bodyweight of the patient.
  • the treatment of infertility may include a step of administering the dose to the patient identified as having the defined serum AMH level and bodyweight.
  • the treatment of infertility may include a step of identifying the patient (prior to treatment) based on the serum AMH level and bodyweight of the patient, and a step of administering the dose to the patient identified (prior to treatment) as having AMH ⁇ 15 pmol/L (for example AMH ⁇ 16 pmol/L, for example AMH ⁇ 19 pmol/L, for example AMH ⁇ 26 pmol/L, for example AMH ⁇ 28 pmol/L, for example AMH ⁇ 40 pmol/L) and identified (prior to treatment) as having bodyweight ⁇ 60 kg [e.g. bodyweight ⁇ 55 kg, for example ⁇ 52 kg, for example ⁇ 50 kg, for example ⁇ 45 kg].
  • AMH ⁇ 15 pmol/L for example AMH ⁇ 16 pmol/L, for example AMH ⁇ 19 pmol/L, for example AMH ⁇ 26 pmol/L, for example AMH ⁇ 28 pmol/L, for example AMH ⁇ 40 pmol/L
  • bodyweight ⁇ 60 kg e.g
  • the step of identifying the patient (prior to treatment) based on the serum AMH level and bodyweight of the patient may take place just before (e.g. 0 to 2 days before) the dose is first administered to the patient.
  • the step of identifying the patient may be based on a serum AMH level determined previously (e.g. a serum AMH level determined up to twelve months before the dose is first administered to the patient).
  • the serum AMH level of the patient is determined (measured) by the ELECSYS AMH Plus immunoassay (available from Roche, of Switzerland, see www.roche.com).
  • the step of identifying the patient may be based on a bodyweight of the patient determined just before (e.g. 0 to 2 days before) the dose is first administered to the patient.
  • the step of determining the bodyweight of the patient may use weighing scales, as are well known.
  • day one of treatment also referred to as “day one of stimulation” refers to the first day that the dose of (e.g. recombinant) FSH is administered to the patient.
  • Day one of treatment may take place on day 1, 2 or 3, preferably day 2 or day 3, of the patient's menstrual cycle.
  • day one of treatment may be one, two or three days, preferably two or three days, after the patient commences menstrual bleeding, as is well known in the art.
  • the dose of FSH starts on day one of treatment and may continue for two to twenty days, for example continue for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days.
  • the dose of FSH starts on day one of treatment and may continue for seven to thirteen days, for example nine to thirteen days, for example 10 to 13 days, for example 10 to 11 days.
  • the dose of FSH may be administered at a dose equivalent to the daily doses mentioned above.
  • the composition may be for administration at a dose of 18 ⁇ g FSH every three days (e.g. for administration on days 1, 4, 7 and so on).
  • composition e.g. pharmaceutical composition
  • medicament may be administered after pre-treatment of the patient with a (different) pharmaceutical composition which suppresses endogenous gonadotropin production prior to day one of the treatment with FSH (e.g. after the subject has been (pre-)treated with a steroid, a GnRH agonist, a GnRH antagonist etc.).
  • pre-treated or “pre-treatment” refers to administration of the pharmaceutical composition which suppresses endogenous gonadotropin production prior to day one of the treatment with FSH and hCG.
  • the composition e.g. pharmaceutical composition
  • medicament may be for administration 12 to 16, e.g. 13 to 15, e.g.
  • a GnRH agonist e.g. Synarel, Lupron, Decapeptyl
  • the product may be for administration with a GnRH agonist.
  • composition e.g. pharmaceutical composition
  • medicament may be for administration prior to administration of a GnRH antagonist (e.g. ganirelix, cetrorelix), for example for administration five or six days prior to administration of a GnRH antagonist.
  • GnRH antagonist e.g. ganirelix, cetrorelix
  • the product may be for administration with a GnRH antagonist.
  • the composition (e.g. pharmaceutical composition) or medicament is for administration prior to administration of a high (ovulatory) dose of hCG (for example 4,000 to 11,000 IU hCG, e.g. 5,000 IU hCG, 10,000 IU hCG etc.; or 150 to 350 microgram recombinant hCG, for example 250 microgram recombinant hCG) to induce final follicular maturation.
  • hCG for example 4,000 to 11,000 IU hCG, e.g. 5,000 IU hCG, 10,000 IU hCG etc.
  • 150 to 350 microgram recombinant hCG for example 250 microgram recombinant hCG
  • the doses above may be for treatment of infertility in the patient's (subject's) first stimulation protocol. It will be appreciated that for further stimulation cycles, the doses may be adjusted according to actual ovarian response in the first cycle.
  • the serum level of AMH may be determined (e.g. measured) by any method known in the art.
  • the serum AMH level may be measured using the AMH Gen-II enzyme linked immunosorbent assay, a kit (Beckman Coulter, Inc., Webster, Tex.). This assay can detect AMH concentrations greater than 0.57 pmol/L with a minimum limit of quantitation of 1.1 pmol/L.
  • the serum AMH level may be measured using the automated AMH ACCESS assay (Beckman Coulter, Inc., Webster, Tex.).
  • the serum AMH level is measured using the Elecsys® AMH assay from Roche Diagnostics. Other assays may be used.
  • treatment of infertility includes treatment of infertility by controlled ovarian stimulation (COS) or methods which include a step or stage of controlled ovarian stimulation (COS), for example Intra Uterine Insemination (IUI), in vitro fertilisation (IVF), or intracytoplasmic sperm injection (ICSI).
  • COS controlled ovarian stimulation
  • IUI Intra Uterine Insemination
  • IVF in vitro fertilisation
  • ICSI intracytoplasmic sperm injection
  • treatment of infertility includes treatment of infertility by ovulation induction (01) or by methods which include a step or stage of ovulation induction (01).
  • treatment of infertility includes treatment of infertility in a subject having tubal or unexplained infertility, including treatment of infertility in a subject having endometriosis, for example stage I or stage II endometriosis, and/or in a subject having anovulatory infertility, for example WHO type II anovulatory infertility, and/or in a subject with a partner with male factor infertility.
  • the product (or composition) may be for (use in) the treatment of infertility (and/or for controlled ovarian stimulation) in a subject having endometriosis, for example in a subject having stage I or stage II endometriosis, as defined by The American Society for Reproductive Medicine (ASRM) classification system for the various stages of endometriosis, (stage IV most severe; stage I least severe) [American Society for Reproductive Medicine. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril 1997; 67,817 821.].
  • ASRM American Society for Reproductive Medicine
  • composition or medicament may be for (use in) the treatment of infertility (and/or for controlled ovarian stimulation) in a subject having normal serum FSH level of 1 to 16 IU/L, for example 1 to 12 IU/L, in the early follicular phase.
  • the composition or medicament may be for (use in) the treatment of infertility (and/or for controlled ovarian stimulation) in a subject aged 18 to 42 years, for example 25 to 37 years.
  • the product may be for (use in) the treatment of infertility (and/or for controlled ovarian stimulation) in a subject having BMI ⁇ 1 and BMI ⁇ 35 kg/m 2 , for example a subject having BMI ⁇ 18 and BMI ⁇ 25 kg/m 2 , for example a subject having BMI ⁇ 20 and BMI ⁇ 25 kg/m 2 .
  • the rFSH may be produced or expressed in a human cell line, for example a Per.C6 cell line, a HEK293 cell line, a HT1080 cell line etc. This may simplify (and render more efficient) the production method because manipulation and control of e.g. the cell growth medium to retain sialylation may be less critical than with known processes.
  • the method may also be more efficient because there is little basic rFSH produced compared to production of known rFSH products; more acidic rFSH is produced and separation/removal of basic FSH is less problematic.
  • the rFSH may be produced or expressed in a PER.C6® cell line, a PER.C6® derived cell line or a modified PER.C6® cell line.
  • rFSH which is produced or expressed in a human cell line (e.g. PER.C6® cell line, HEK293 cell line, HT1080 cell line etc.) will include some ⁇ 2,6-linked sialic acids ( ⁇ 2,6 sialylation) provided by endogenous sialyl transferase activity [of the cell line] and will include some ⁇ 2,3-linked sialic acids ( ⁇ 2,3 sialylation) provided by endogenous sialyl transferase activity.
  • the cell line may be modified using ⁇ 2,3-sialyltransferase.
  • the cell line may be modified using ⁇ 2,6-sialyltransferase.
  • the rFSH may include ⁇ 2,6-linked sialic acids ( ⁇ 2,6 sialylation) provided by endogenous sialyl transferase activity [of the cell line].
  • ⁇ 2,6 sialylation endogenous sialyl transferase activity [of the cell line].
  • human derived recombinant FSH means recombinant FSH which is produced or expressed in a human cell line (e.g. recombinant FSH made by engineering a human cell line).
  • the rFSH may be produced using ⁇ 2,3- and/or ⁇ 2,6-sialyltransferase.
  • rFSH is produced using ⁇ 2,3-sialyltransferase.
  • the rFSH may include ⁇ 2,6-linked sialic acids ( ⁇ 2,6 sialylation) provided by endogenous sialyl transferase activity.
  • the composition may be a pharmaceutical composition.
  • the pharmaceutical composition is for the treatment of infertility.
  • the treatment of infertility may comprise assisted reproductive technologies (ART), ovulation induction or intrauterine insemination (IUI).
  • ART assisted reproductive technologies
  • IUI intrauterine insemination
  • the pharmaceutical composition may be used, for example, in medical indications where known FSH preparations are used.
  • composition or medicament can be formulated into well-known compositions for any route of drug administration, e.g. oral, rectal, parenteral, transdermal (e.g. patch technology), intravenous, intramuscular, subcutaneous, intrasusternal, intravaginal, intraperitoneal, local (powders, ointments or drops) or as a buccal or nasal spray.
  • route of drug administration e.g. oral, rectal, parenteral, transdermal (e.g. patch technology), intravenous, intramuscular, subcutaneous, intrasusternal, intravaginal, intraperitoneal, local (powders, ointments or drops) or as a buccal or nasal spray.
  • a typical composition comprises a pharmaceutically acceptable carrier, such as aqueous solution, non toxic excipients, including salts and preservatives, buffers and the like, as described in Remington's Pharmaceutical Sciences fifteenth edition (Matt Publishing Company, 1975), at pages 1405 to 1412 and 1461-87, and the national formulary XIV fourteenth edition (American Pharmaceutical Association, 1975), among others.
  • a pharmaceutically acceptable carrier such as aqueous solution, non toxic excipients, including salts and preservatives, buffers and the like, as described in Remington's Pharmaceutical Sciences fifteenth edition (Matt Publishing Company, 1975), at pages 1405 to 1412 and 1461-87, and the national formulary XIV fourteenth edition (American Pharmaceutical Association, 1975), among others.
  • aqueous and non-aqueous pharmaceutical carriers, diluents, solvents or vehicles examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
  • the compositions or medicaments of the present invention also can contain additives such as but not limited to preservatives, wetting agents, emulsifying agents, surfactants and dispersing agents.
  • Antibacterial and antifungal agents can be included to prevent growth of microbes and includes, for example, m-cresol, benzyl alcohol, paraben, chlorobutanol, phenol, sorbic acid, and the like. If a preservative is included, benzyl alcohol, phenol and/or m-cresol are preferred; however, the preservative is by no means limited to these examples. Furthermore, it may be desirable to include isotonic agents such as sugars, sodium chloride, and the like.
  • composition or medicament may further comprise a salt comprising a pharmaceutically acceptable alkali metal cation selected from the group consisting of Na + - or K + -salts, or a combination thereof.
  • a salt comprising a pharmaceutically acceptable alkali metal cation selected from the group consisting of Na + - or K + -salts, or a combination thereof.
  • the salt is a Na + -salt, for example NaCl or Na 2 SO 4 .
  • composition or medicament comprises recombinant FSH and one or more of Polysorbate 20, L-methionine, phenol, disodium sulphate and sodium phosphate buffer.
  • FSH FSH
  • other active ingredients if present
  • This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility.
  • the rate of absorption of FSH then depends upon its rate of dissolution which, in turn, can depend upon crystal size and crystalline form.
  • delayed absorption of a parenterally administered FSH combination form is accomplished by dissolving or suspending the FSH combination in an oil vehicle.
  • injectable depot forms can be made by forming microencapsule matrices of the FSH (and other agents, if present) in biodegradable polymers such as polylactide-polyglycolide.
  • the rate of FSH release can be controlled.
  • biodegradable polymers include polyvinylpyrrolidone, poly(orthoesters), poly(anhydrides) etc.
  • Depot injectable formulations are also prepared by entrapping the FSH in liposomes or microemulsions which are compatible with body tissues.
  • Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • Injectable formulations can be supplied in any suitable container, e.g. vial, pre-filled syringe, injection cartridges, and the like.
  • the composition or medicament may be formulated for single use or for multiple use (multiple dose). If the composition or medicament is formulated for multiple use, it is preferred that a preservative is included. If a preservative is included, benzyl alcohol, phenol and/or m-cresol are preferred; however, the preservative is by no means limited to these examples.
  • the single use or multiple use formulated composition or medicament may further comprise a salt comprising a pharmaceutically acceptable alkali metal cation selected from the group consisting of Na + - or K + -salts, or a combination thereof.
  • the salt is a Na + -salt, for example NaCl or Na 2 SO 4 .
  • composition or medicament may be included in a container such as a vial, prefilled cartridge (e.g. for single administration or multiple use) or an injection device such as a “pen” for e.g. administration of multiple doses.
  • a container such as a vial, prefilled cartridge (e.g. for single administration or multiple use) or an injection device such as a “pen” for e.g. administration of multiple doses.
  • the composition or medicament may be a formulation (e.g. injectable formulation) including FSH (optionally with hCG, LH, LH activity etc.)
  • the LH activity may originate from LH or human chorionic gonadotropin, hCG. If there is more than one active ingredient (i.e. FSH and e.g. hCG or LH) these may be suitable for administration separately or together. If administered separately, administration can be sequential.
  • the composition or medicament can be supplied in any appropriate package.
  • a composition or medicament can include a number of containers (e.g. pre-filled syringes or vials) containing either FSH or hCG, or a combination (or combination) of both FSH and hCG.
  • the hCG may be recombinant hCG or urinary hCG.
  • the composition or medicament includes a number of containers (e.g. pre-filled syringes or vials) containing FSH, e.g. recombinant FSH, each container may include the same amount of FSH.
  • One or more containers may include different amounts of FSH.
  • the syringes or vials may be packaged in a blister package or other means to maintain sterility.
  • Any composition or medicament can optionally contain instructions for using the FSH (and e.g. hCG if present) formulations.
  • the pH and exact concentration of the various components of the pharmaceutical composition are adjusted in accordance with routine practice in this field.
  • compositions or medicament of the invention are supplied as compositions for parenteral administration.
  • General methods for the preparation of the parenteral formulations are known in the art and are described in REMINGTON; THE SCIENCE AND PRACTICE OF PHARMACY, supra, at pages 780-820.
  • the parenteral compositions can be supplied in liquid formulation or as a solid which will be mixed with a sterile injectable medium just prior to administration.
  • the parenteral compositions are supplied in dosage unit form for ease of administration and uniformity of dosage.
  • a method of treatment of infertility comprising: a step of administering a daily dose of, or a daily dose equivalent to, 6 to 8 ⁇ g recombinant FSH, to a patient (e.g. a female patient) having AMH 15 pmol/L (for example AMH ⁇ 16 pmol/L, for example AMH ⁇ 19 pmol/L, for example AMH ⁇ 26 pmol/L, for example AMH ⁇ 28 pmol/L, for example AMH ⁇ 40 pmol/L) and bodyweight ⁇ 60 kg [e.g. bodyweight ⁇ 55 kg, for example ⁇ 52 kg, for example ⁇ 50 kg, for example ⁇ 45 kg, for example ⁇ 42 kg, for example ⁇ 31.5 kg].
  • the daily dose is 6 to 8 ⁇ g recombinant FSH. More preferably, the daily dose is 6 ⁇ g recombinant FSH.
  • the method may include a step of determining the serum AMH level and bodyweight of the patient.
  • the method may include a step of administering the dose to the patient having the defined serum AMH level and bodyweight.
  • the method may include a step of determining the serum AMH level and bodyweight of the patient, and a step of administering the dose to the patient having AMH ⁇ 15 pmol/L (for example AMH ⁇ 16 pmol/L, for example AMH 19 pmol/L, for example AMH ⁇ 26 pmol/L, for example AMH ⁇ 28 pmol/L, for example AMH ⁇ 40 pmol/L) and bodyweight ⁇ 60 kg (e.g. bodyweight ⁇ 55 kg, for example ⁇ 52 kg, for example ⁇ 50 kg, for example ⁇ 45 kg, for example ⁇ 42 kg, for example ⁇ 31.5 kg).
  • a method of treatment of infertility comprising a step of administering a daily dose of, or a daily dose equivalent to, 6 to 8 ⁇ g recombinant FSH to a patient (e.g. a female patient) identified (prior to treatment) as having AMH ⁇ 15 pmol/L (for example AMH ⁇ 16 pmol/L, for example AMH ⁇ 19 pmol/L, for example AMH ⁇ 26 pmol/L, for example AMH ⁇ 28 pmol/L, for example AMH ⁇ 40 pmol/L) and identified (prior to treatment) as having bodyweight ⁇ 60 kg (e.g.
  • the daily dose is 6 to 8 ⁇ g recombinant FSH. More preferably, the daily dose is 6 ⁇ g recombinant FSH.
  • the method may include a step of identifying the patient (prior to treatment) based on the serum AMH level and bodyweight of the patient.
  • the method may include a step of administering the dose to a patient identified as having the defined serum AMH level and bodyweight.
  • the method may include a step of identifying the patient (prior to treatment) based on the serum AMH level and bodyweight of the patient, and a step of administering the dose to the patient identified (prior to treatment) as having AMH ⁇ 15 pmol/L (for example AMH ⁇ 16 pmol/L, for example AMH ⁇ 19 pmol/L, for example AMH ⁇ 26 pmol/L, for example AMH ⁇ 28 pmol/L, for example AMH ⁇ 40 pmol/L) and identified (prior to treatment) as having bodyweight ⁇ 60 kg [e.g. bodyweight ⁇ 55 kg, for example ⁇ 52 kg, for example ⁇ 50 kg, for example ⁇ 45 kg].
  • the method may be for use for treatment of infertility in an Asian (e.g. Japanese, Chinese, Korean, Indian) patient.
  • Asian e.g. Japanese, Chinese, Korean, Indian
  • the patient has (is identified as having) bodyweight ⁇ 52 kg (for example ⁇ 50 kg, for example ⁇ 45 kg) and has (is identified as having) AMH ⁇ 26 pmol/L (for example AMH ⁇ 28 pmol/L, for example AMH ⁇ 30 pmol/L, for example AMH ⁇ 40 pmol/L).
  • bodyweight ⁇ 52 kg for example ⁇ 50 kg, for example ⁇ 45 kg
  • AMH ⁇ 26 pmol/L for example AMH ⁇ 28 pmol/L, for example AMH ⁇ 30 pmol/L, for example AMH ⁇ 40 pmol/L.
  • the FSH is a recombinant FSH (rFSH).
  • the rFSH e.g. human cell line derived recombinant FSH
  • the FSH (rFSH) for use according to the invention may have 1% to 99% of the total sialylation being ⁇ 2,3-sialylation.
  • the FSH (rFSH) according to the invention may have 1% to 99% of the total sialylation being ⁇ 2,6-sialylation.
  • 80 to 95%, for example 80 to 90%, for example 82 to 89%, for example 85 to 89% of the total sialylation is ⁇ 2,3-sialylation.
  • sialylation it is meant the amount of sialic residues present on the FSH carbohydrate structures.
  • ⁇ 2,3-sialylation means sialylation at the 2,3 position (as is well known in the art) and ⁇ 2,6 sialylation at the 2,6 position (also well known in the art).
  • % of the total sialylation may be a 2,3 sialylation” refers to the % of the total number of sialic acid residues present in the FSH which are sialylated in the 2,3 position.
  • % of the total sialylation being ⁇ 2,6-sialylation refers to the % of the total number of sialic acid residues present in the FSH which are sialylated in the 2,6 position.
  • the rFSH may be present as a single isoform or as a mixture of isoforms.
  • a composition for use in the treatment of infertility in a patient having AMH ⁇ 26 pmol/L and bodyweight ⁇ 52 kg comprising a daily dose of 6 to 8 ⁇ g recombinant FSH.
  • the patient has (is identified as having) bodyweight ⁇ 52 kg (for example ⁇ 50 kg, for example ⁇ 45 kg) and has (is identified as having) AMH ⁇ 26 pmol/L (for example AMH ⁇ 28 pmol/L, for example AMH ⁇ 30 pmol/L, for example AMH ⁇ 40 pmol/L).
  • a composition for use in the treatment of infertility in a patient having AMH ⁇ 26 pmol/L and bodyweight ⁇ 61 kg comprising a daily dose of, or a daily dose equivalent to, 6 to 8 ⁇ g recombinant FSH.
  • the patient has (is identified as having) bodyweight ⁇ 52 kg (for example ⁇ 50 kg, for example ⁇ 45 kg) and has (is identified as having) AMH ⁇ 26 pmol/L (for example AMH 28 pmol/L, for example AMH ⁇ 30 pmol/L, for example AMH ⁇ 40 pmol/L).
  • FIG. 1 presents the body weight and AMH of all patients in the Japanese Phase II clinical trial discussed in the retrospective analysis of Example 3, and indicates whether the dose protocol set out in Table A above would specify a dose of ⁇ 6 ⁇ g Rekovelle® (diamonds) or ⁇ 6 ⁇ g Rekovelle.
  • Rekovelle® is a recombinant FSH expressed in a PER.C6® cell line engineered by the methods disclosed in WO2013/020996 and WO2009/127826A.
  • the Marketing Authorisation holder for Rekovelle® is Ferring Pharmaceuticals NS of Kay Fiskers Plads 11, 2300 Copenhagen S, Denmark, and it is available in the UK from Ferring Pharmaceuticals of Drayton Hall, Church Road, West Drayton, UB7 7PS, UK
  • Rekovelle® The active substance in Rekovelle® is follitropin delta (FE999049).
  • Rekovelle is highly sialylated and includes ⁇ 2,3- and ⁇ 2,6-sialylation, with about 85% to 90% of the total sialylation being ⁇ 2,3-sialylation and about 10% to 15% of the total sialylation being ⁇ 2,6-sialylation.
  • REKOVELLE is a clear and colourless solution for injection (injection). It is available in packs of 1 cartridge and 3 pen injection needles. Each multidose cartridge contains 12 micrograms of follitropin delta in 0.36 millilitre of solution. One millilitre of solution contains 33.3 micrograms of follitropin delta in each millilitre of solution.
  • the other ingredients are phenol, polysorbate 20, L-methionine, sodium sulphate decahydrate, disodium phosphate dodecahydrate, concentrated phosphoric acid, sodium hydroxide and water for injections.
  • EXAMPLE 2 A RANDOMISED, ASSESSOR-BLIND, (AMH)-STRATIFIED, DOSE RESPONSE TRIAL IN JAPANESE IVF/ICSI PATIENTS UNDERGOING CONTROLLED OVARIAN STIMULATION WITH FOLLITROPIN DELTA
  • a randomised, controlled, assessor-blind, parallel groups, multi-centre phase 2 anti-Müllerian hormone (AMH)-stratified trials was conducted in IVF/ICSI patients in Japan, with the purpose of determining the dose-response relationship of FE 999049 and the number of oocytes retrieved. Randomisation was stratified according to AMH levels at screening; low AMH (5.0-14.9 pmol/L) or high AMH (15.0-44.9 pmol/L).
  • FE 999049 There were 158 patients, 20 to 39 years (mean age 33.7 years) undergoing COS with three dose levels of FE 999049, follitropin delta (Ferring Pharmaceuticals).
  • the doses of FE 999049 were 6 ⁇ g/day, 9 ⁇ g/day and 12 ⁇ g/day and a standard therapy of the approved rFSH product (FOLLISTIM, MSD, 150 IU/day) was also included as control.
  • FOLLISTIM follitropin beta
  • the daily dose was fixed throughout the stimulation period. A statistically significant dose response relationship for FE 999049 with respect to the number of oocytes retrieved was observed for the overall population and for each AMH randomisation stratum. Acceptable pregnancy rates were achieved with all FE 999049 doses.
  • the dose protocol set out in Table A above goes some way to mitigating this risk because patients are dosed by bodyweight.
  • very low doses of gonadotropins are potentially associated with inadequate follicular recruitment and poor ovarian response.
  • dosing according to the Table A protocol might lead to very light patients with high AMH receiving a dose of FSH which may be sub-optimal from an efficacy perspective.
  • the total number of patients with early OHSS was 4 (13.8%) in the 6 ⁇ g FE 999049 group and 8 (24.2%) in the 150 IU FOLLISTIM group.
  • Early moderate/severe OHSS was reported for 3 (10.3%) patients and 7 (21.2%) patients in the 6 ⁇ g FE 999049 and 150 IU FOLLISTIM groups, respectively.
  • oocyte yield above the appropriate response of 8-14 oocytes was only observed in 1 (3.4%) patient in the 6 ⁇ g FE 999049 group in contrast to 7 (21.2%) patients in the 150 IU FOLLISTIM group.
  • Table 1 covers all patients with body weight ⁇ 60 kg, independent of AMH level. All patients with AMH ⁇ 15 pmol/L will receive 12 ⁇ g FE 999049. The situation where a patient may have a calculated dose ⁇ 6 ⁇ g but will receive 6 ⁇ g is therefore only applicable to patients with AMH ⁇ 15 pmol/L. Data on patients in the Japanese phase 2 trial who had body weight ⁇ 60 kg and AMH ⁇ 15 pmol/L are presented in Table 2.
  • the total number of patients with early OHSS was 4 (22.2%) in the 6 ⁇ g FE 999049 group and 7 (31.8%) in the 150 IU FOLLISTIM group.
  • Moderate/severe OHSS was the most common severity among the early OHSS cases and was reported for 3 (16.7%) patients in the 6 ⁇ g FE 999049 group and 6 (27.3%) patients in the 150 IU FOLLISTIM group.
  • the frequency of adverse events judged by the investigator to be related to the drug used for controlled ovarian stimulation was 20.7% in the 6 ⁇ g FE 999049 group and 33.3% in the 150 IU FOLLISTIM group.
  • the frequency of related adverse events was 27.8% in the 6 ⁇ g FE 999049 group and 36.4% in the 150 IU FOLLISTIM group.
  • the clinical pregnancy rate per cycle with transfer in patients with body weight ⁇ 60 kg was 40.0% in the 6 ⁇ g FE 999049 group and 21.7% in the standard therapy group.
  • the clinical pregnancy rate per cycle with transfer was 38.5% and 20.0% in the 6 ⁇ g FE 999049 and standard therapy groups, respectively.
  • FIG. 1 shows these 18 patients with small diamonds (rather than squares) to the bottom right of the FIG.
  • the mean calculated dose is 5.33 ⁇ g and the proposed dosing regimen amounts thus to a 13% higher mean dose compared to the regimen without a minimum (mean dose 6.0 ⁇ g instead of 5.33 ⁇ g).
  • the ovarian response is expected to be beneficially influenced by implementing 6 ⁇ g as the minimum dose.
  • 6 ⁇ g is the minimum dose (48.0% of patients, versus 44.8% with the regimen without a minimum dose), as shown in Table 3.
  • model predictions of the ovarian response with the proposed dosing regimen further support the appropriateness of a minimum dose of 6 ⁇ g.
  • the proposed FE 999049 dosing regimen including the implementation of 6 ⁇ g as the minimum dose, is safe and efficacious, and is proposing this for the phase 3 trial in Japan.
  • Phase 3 data on Japanese patients with a calculated dose ⁇ 6 ⁇ g will be analysed specifically for the purpose of PMDA review to support the efficacy and safety of 6 ⁇ g FE 999049 in these patients.
  • the trial has been designed to demonstrate non-inferiority of FE 999049 versus an rFSH product approved in Japan, i.e. FOLLISTIM, with respect to number of oocytes retrieved.
  • Subjects will be screened within 60 days prior to start of stimulation for compliance with the inclusion and exclusion criteria. On day 2-3 of the menstrual cycle, subjects will be randomised in a 1:1 ratio to controlled ovarian stimulation with FE 999049 or FOLLISTIM. Randomisation will be stratified by centre and according to AMH levels at screening ( ⁇ 15 pmol/L and ⁇ 15 pmol/L).
  • Subjects randomised to FE 999049 will have their individual FE 999049 dose determined on the basis of their AMH level at screening and their body weight at start of stimulation (see below).
  • the daily FE 999049 dose will be fixed throughout the stimulation period.
  • the daily FE 999049 dose is 12 ⁇ g, irrespective of body weight.
  • the daily FE 999049 dose is on a continuous scale ranging from 0.19 to 0.10 ⁇ g/kg, i.e. dependent on actual AMH and body weight. This is set out in the Table below.
  • the minimum allowed daily FE 999049 dose is 6 ⁇ g and the maximum allowed daily FE 999049 dose is 12 ⁇ g.
  • Subjects can be treated with FE 999049 for a maximum of 20 days, and coasting is not allowed.
  • the dosing regimen is within labelling (see below).
  • the starting dose of FOLLISTIM is 150 IU and fixed for the first five stimulation days after which it may be adjusted by 75 IU based on the individual response.
  • the maximum daily FOLLISTIM dose allowed is 375 IU.
  • Subjects can be treated with FOLLISTIM for a maximum of 20 days, and coasting is not allowed.
  • a GnRH antagonist will be initiated on stimulation day 6 at a daily dose of 0.25 mg and continued throughout the stimulation period. Triggering of final follicular maturation will be done with 5,000 IU urinary human chorionic gonadotropin (hCG) on the day when ⁇ 3 follicles with a diameter ⁇ 17 mm are observed.
  • hCG urinary human chorionic gonadotropin
  • Oocyte retrieval will take place 36 h ( ⁇ 2 h) after triggering of final follicular maturation and the oocytes can be inseminated by IVF or ICSI. Fertilisation and embryo development will be assessed from oocyte retrieval to the day of transfer. One blastocyst of the best quality available will be transferred on day 5 after oocyte retrieval while remaining blastocysts may be cryopreserved. For subjects who underwent triggering of final follicular maturation with GnRH agonist, no transfer will take place and blastocysts may instead be cryopreserved on day 5. All cryopreserved blastocysts can be used by the subject after completion of the trial, in accordance with the declaration by Japan Society of Obstetrics and Gynaecology (JSOG).
  • JSOG Japan Society of Obstetrics and Gynaecology
  • Vaginal progesterone tablets 100 mg three times daily will be provided for luteal phase support from the day after oocyte retrieval until the day of the clinical pregnancy visit.
  • Luteal phase support will only be provided to subjects planned to undergo transfer and can be terminated earlier in case of no transfer or a negative ⁇ hCG test.
  • a ⁇ hCG test is performed 13-15 days after transfer followed by a transvaginal ultrasound 5-6 weeks after transfer to assess clinical and vital pregnancy.
  • Blood samples will be collected during the trial for the purpose of evaluating the endocrine profile as well as clinical chemistry and haematology parameters.
  • Endocrine parameters are measured at screening, stimulation day 1, stimulation day 6 and end-of-stimulation.
  • Clinical chemistry and haematology parameters are assessed at screening, end-of-stimulation and end-of-trial.
  • Local tolerability of FE 999049 following subcutaneous administration will be assessed by the subjects three times daily: immediately, 30 minutes and 24 hours after the injection. The assessment of injection site reactions will be made throughout the stimulation period and recorded by the subjects in a diary.
  • the procedures and/or assessments can be postponed to the upcoming weekday (maximum one day after original visit schedule) or cancelled, if appropriate.
  • pregnancy progress and outcome data will be gathered for subjects with a vital pregnancy. Data will be collected on ongoing pregnancy (10-11 weeks after transfer) and pregnancy outcome as well as neonatal health at birth and at 4 weeks after birth. The pregnancy follow-up does not include any interventions but only data collection.
  • the pregnancy follow-up data will be based on reports obtained from the subject's gynaecologist/obstetrician and the subject's Maternal and Child Health Handbook. The data will be retrieved by the trial site, either via the subject's gynaecologist/obstetrician, the subject herself, or other sources, as applicable.
  • Ferring intends to submit the J-NDA following completion of the main part of the trial (i.e. up to the clinical pregnancy visit), and to include the pregnancy follow-up data available at that time in the J-NDA.
  • the pregnancy follow-up data can be submitted after completion.
  • Infertility for at least 1 year before randomisation (not applicable in case of tubal or severe male factor infertility).
  • the trial cycle will be the subject's first controlled ovarian stimulation cycle for IVF/ICSI.
  • Known history of recurrent miscarriage (defined as three consecutive losses after ultrasound confirmation of pregnancy (excl. ectopic pregnancy) and before week 24 of pregnancy). 4.
  • Known abnormal karyotype of subject or of her partner In case the sperm production is severely impaired (concentration ⁇ 1 million/mL), normal karyotype, including no Y-chromosome microdeletion, must be documented. 5.
  • Known porphyria 7. Any known clinically significant systemic disease (e.g. insulin-dependent diabetes).
  • Known inherited or acquired thrombophilia disease 9.
  • Any known endocrine or metabolic abnormalities (pituitary, adrenal, pancreas, liver or kidney) which can compromise participation in the trial with the exception of controlled thyroid function disease. 10.
  • Known presence of anti-FSH antibodies (based on the information available in the subject's medical records).
  • Known moderate or severe impairment of renal or hepatic function 14.
  • breast-feeding 15. Undiagnosed vaginal bleeding. 16.
  • subjects On day 2-3 of the menstrual cycle, subjects will be randomised in a 1:1 ratio to treatment with either FE 999049 or FOLLISTIM, and controlled ovarian stimulation will be initiated.
  • Subjects randomised to FE 999049 will have their individual dose determined on the basis of their AMH level at screening and their body weight at randomisation. For subjects with AMH ⁇ 15 pmol/L the daily FE 999049 dose is 12 ⁇ g, irrespective of body weight. For subjects with AMH ⁇ 15 pmol/L the daily FE 999049 dose is on a continuous scale ranging from 0.19 to 0.10 ⁇ g/kg, i.e. dependent on actual AMH and body weight.
  • the daily FE 999049 dose will be fixed throughout the stimulation period.
  • the minimum allowed daily FE 999049 dose is 6 ⁇ g.
  • the maximum allowed daily FE 999049 dose is 12 ⁇ g. Dosing will continue until the criterion for triggering of final follicular maturation has been met. Subjects can be treated with FE 999049 for a maximum of 20 days. Coasting is not allowed.
  • the FE 999049 preparation is administered as a single daily subcutaneous injection in the abdomen.
  • the dose must not be split into two injections. To minimise local injection site reactions, it is advisable to change injection site regularly.
  • the first FE 999049 injection will take place at the clinic and will be performed either by the trial medication delegate or the subject under supervision by the trial medication delegate. Subsequent injections can be done at home or at the clinic.
  • the trial medication delegate will give the subject instructions for how to administer FE 999049.
  • the subject's serum AMH concentration will be available from the blood sample taken at screening and analysed by a central laboratory using Elecsys® AMH assay from Roche Diagnostics.
  • the AMH concentration will be provided from the central laboratory directly to the eCRF.
  • the subject's body weight will be measured at randomisation using a calibrated scale and performed without shoes and overcoat. The body weight result will be entered into the eCRF.
  • the FE 999049 dosing algorithm has been programmed in the eCRF, which calculates the FE 999049 dose based on the subject's AMH and body weight.
  • the FE 999049 pre-filled injection pen is intended for subcutaneous administration of FE 999049. It is a non-sterile needle-based disposable device with integrated non-replaceable 3 mL cartridge containing the liquid FE 999049 drug product. Each cartridge holds multiple doses, the size of which are adjustable by the user. It is possible to set doses from 0.33 ⁇ g to 20.0 ⁇ g in increments of 0.33 ⁇ g.
  • the FE 999049 pre-filled injection pen has a dosing scale numbered from 0 to 20 ⁇ g. Each number is separated by two lines, each line representing 0.33 ⁇ g. The pre-filled injection pen can be set to deliver doses rounded to the nearest 0.33 ⁇ g.
  • Rounding off of the calculated dose may be needed, as in this example of a subject weighing 75.0 kg with an AMH level of 35 pmol/L for whom the calculated dose is 8.25 ⁇ g (0.11 ⁇ g/kg*75.0 kg), which will then be rounded to 8.33 ⁇ g, i.e. 8 ⁇ g+1 line on the pen.
  • the eCRF will provide the calculated dose in an output that matches the numbers and lines on the pre-filled injection pen; i.e. any rounding off will be done automatically prior to providing the subject's calculated dose.
  • the trial medication delegate will be instructed and trained in the correct use of the pre-filled injection pen, so that correct instructions can be provided to the subject.
  • the dosing regimen is within labelling.
  • the starting dose of FOLLISTIM is 150 IU and fixed for the first five stimulation days, after which it may be adjusted by 75 IU based on the individual response.
  • the maximum daily FOLLISTIM dose allowed is 375 IU. Dosing will continue until the criterion for triggering of final follicular maturation has been met. Subjects can be treated with FOLLISTIM for a maximum of 20 days. Coasting is not allowed.
  • the FOLLISTIM dosing regimen is shown in detail in the following Table.

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